Literature Review

Hunter’ssyndrome and oral manifestations:a review

Angela TempletonDowns, DDSTim Crisp, DMDGerald Ferretti, DDS, MS

Abstract Wereview the literature considering systemic and Reviewof the literature on Hunter’s syndromeand oral oral manifestations of children diagnosed with Hunter’s manifestations in pediatric dental patients including the . We review a mode of treatment for these primary and secondary systemic manifestations are pre- patients as well. sented. Numerousoral manifestations are presented as Literature review well. Basedon the cases presentedin the reviewedstudies, 6 little informationis available on oral considerations and Charles Hunter noted a rare disease in children as treatment of these children. Early restoration of the oral early as 1915. On 8- and 10-year-old brothers, he re- cavity is importantprior to treatmentof the disease itself. ported findings such as a slowed learning process, (Pediatr Dent 17:98-100, 1995) throat trouble, tonsil and adenoid operations, dull hear- ing, inguinal , short stature, curiously shaped unter’s syndrome is an X-linked recessive heads, large faces, puffy eyes, saddle nose, thick lips, mucopolysaccharide disorder caused by a open mouths, large , abducted arms, thick H defect in the of glycosaminogly- wrists, and a very clumsyand stiff gait. These children also suffer from increasingly frequent and severe res- cans, which results from a deficiency of the ~, iduronate sulfatase. There is an accumulation of piratory infections 2, 6 that generally increase with age. dermatan and heparan sulfates in various tissues. This syndrome is found in fewer than 20 cases per Mild and severe forms exist that are a result of mu- million births, makingthe disease the rarest form of the tagenic . Hunter’s syndromeclinically resembles mucopolysaccharide disorders as reported by other mucopolysaccharide disorders such as Hurler’s, Dorfman2Carrier females generally are asymptomatic, San Filippo’s, Morquio’s, and Schere’s , though they often show decreased levels of iduronate which are autosomal recessive. Hunter’s syndrome sulfatase in serum. Clinical manifestations of Hunter’s syndrome in females are exceedingly rare with only a is the exception being transmitted as an X-linked 1’ recessive1-6 disorder. few cases reported. 12 Clarke et al22 reported the syn- Primary systemic manifestations of Hunter’s syn- dromein a karyotypically normal girl. Neufeld et a123 drome are: reported two girls with clinical manifestations of type II and enzyme deficien- 1. cies as well as a normal karyotype. There may be no 2. Moderate to severe developmental delay family history of mucopolysaccharide disorders when 3. Dysmorphic facies a child is diagnosed with one. Successive births or numerouschildren mayresult in a family having more 4. Skeletal abnormalities than one child with the syndromebefore the first one 5. contractures has any physical signs or has been diagnosed. Despite 6. , manypeople continue to have chil- 7. Cardiac valvular disease dren affected by this type of disorder. There are two forms of Hunter’s syndrome. Type A 8. Hirsutism is the most severe form with a life expectancy of 14-15 9. Hyperkinesis years and a muchearlier onset. Type B is a muchmilder 10. Rough and uncoordinated behavior. form with a life expectancyof 30-50 years1, 2 and physi- cal features similar to, but not as severe as those of Secondarysystemic manifestations are frequent otitis Type A. Yatziv et al.14 suggested that the presence or mediaand hearing insufficiencies. 1-3, 6-9 absence of severe mental retardation and the longevity Oral manifestations include short and broad man- of the affected individuals be distinguishing factors in dible; localized, radiolucent lesions of the jaws; flat- order to help clinically determine the difference be- tened temporomandibular ; macroglossic ; tween these two forms. Younget al.15 established that conical, peg-shaped teeth with generalized wide spac- patients with Hunter’s syndromedid clearly fall into ing; highly arched palate with flattened alveolar ridges; one of two groups according to the presence or absence andhyperplastic gingiva. 1, 2, 6, 7, 10, 11 of intellectual deterioration. They also reported the

98 AmericanAcademy of PediatricDentistry PediatricDentistry - 17:2,1995 more severely affected patients showeda higher inci- sions usually are associated with unerupted first per- dence of behavioral disorders. manent molars. Lit117 and Gardner7 reported that based DorfmanI has reported Hunter’s syndrome to be on other studies that these enlarged dental follicles characterized by the accumulation of dermatan and represented pools of B (dermatan in various tissues and can be diag- sulfate). Gardner7 and Stewart et al. 1° noted that these nosed if there is found to be more dermatan than lesions contain dense, fibrous connective tissues and heparan in tissues; while in Hurler’s syndrome,heparan large amounts of acid mucopolysaccharides. These ar- is more abundant. Other diagnostic characteristics in- eas of destruction also tend to worsen with age. The clude the patient’s physical features; dysostosis; gingival tissues are hyperplastic, hypertrophic, and dermatan or heparan in urine; enzyme studies show- enlarged, while the tongue is thickened and ing iduronate sulfatase deficiency in serum, white blood macroglossic2,2, 6, 7,10 The goal wouldbe to extract any cells, or cultured fibroblasts.1~ 2 cystically involved teeth, restore any carious teeth, and Hunter6 reported what have become the classical maintain oral health. Antibiotics should be given as a features of the syndrome bearing his name. The many prophylatic measure due to the conditions asso- primary systemic manifestations of Hunter’s syndrome ciated with Hunter’s syndrome. include macrocephaly, with the skull thickened and The temporomandibularjoint often shows a flatten- deformed, and the cranial base and orbital roofs be- ing of the articular surface, while the condyle maybe come thick and dense with the sagittal and lamboidal flattened or reduced in size accompanied by a large sutures closing prematurely. Very prominent frontal coronoid7 process with hypomotility. bossing and temporal bulges, as well as changes in the The teeth are small and shortened. There is general- skull can be present. As the children grow, they exhibit ized wideinterdental spacing.R, 6, 7,10,17 Theteeth can be moderate to severe developmental delay with peg-shaped and conical and often hypoplastic. Ante- hyperkinesis along with rough and uncoordinated be- 7 rior open-bites have been noted due to the enlarged havior.L2, 6, 7, 14, is Gardnerreportedthat these children protruding tongues, y, 17 There is delayed root forma- show resistance to discipline and are stubborn and tion, and the molars are often further posterior with a fearless, and becomeso difficult to managethat they distoangular tipping. 7 The palate is highly arched in are generally institutionalized. Their ability to speak manypatients with prominent palatal rugae. There are and walk decreases with age. He also noted that they deep grooves in the midsagittal plane and the alveolar have progressive difficulty in eating solid food and ridges are flattened7 The gingival tissues are that weight loss is common. hyperplastic, hypertrophic, and enlarged, while the Hunter6 and Dorfman1 reported problems with ton- tongueis thickenedand macroglossic.1, 2, 6, 7,10 sils and adenoids leading to frequent and severe respi- Hunter’s syndrome is diagnosed by a presence of ratory infections. Morehead and Parsons16 have re- the classical features reported by Hunter,6 Gorlin,2 and ported tracheobronchomalacia/major airway collapse. Dorfman2Clinical examinations, skeletal surveys, urine Skeletal abnormalities include an enlarged chest with and serum iduronate sulfatase analysis, psychomotor flaring ribs and short stature. The abnormalextremities tests, and genetic evaluations all have been used in show broad, claw-like short fingers. These children confirming Hunter’s syndrome2,2, 4, s exhibit hepatosplenomegaly due to the accumulation marrow transplant (BMT) has been consid- of dermatan and heparan, which also causes cardiac ered a possible mode of treatment in patients with valvular disease resulting in distortion of the heart mucopolysaccharidosisbecause this is a stem dis- valves and thickening of the coronary arteries. Hirsutism order. 19 Warkentin et al. 2° reported that a BMTcould is noted and usually increases after age 2.1-3, 6 serve as a permanentsource of normal cells capable of Secondary systemic manifestations include frequent producing the deficient enzyme. This would permit otitis media resulting in hearing insufficiencies and the affected cells to degrade accumulated glycosami- progressive deafness.1-3, 6 noglycans and prevent further deposition. In BMT,lethal doses of chemotherapyand total body Death usually occurs due to cardiac or 16respiratory arrest.l-3, 6, 14 Morehead and Parsons reported radiation are used to completely destroy all bone mar- tracheobronchomalaciato be a part of respiratory com- row elements -- both malignant and normal cell lines plications. Liu17 and Gardner7 have reported that the -- thereby eliminating the inborn error of metabolism. mandible of the Hunter’s syndromepatient is usually A healthy donor’s cells are used to repopulate the mar- short and broad with a wide intergonial distance; and row with normal cells. This procedure is not retroac- the distance around the arch is larger, resulting in in- tive19 but can prevent progression. creased interdental spacing. Gardner7 has noted that Recommendation for BMTdepends on age, com- the rami are often short and narrow. patibility of donor, degree of cardiac and in- The localized lesions of the jaws often resemble volvement, and parental consent. The prognosis is dif- dentigerous cysts and are usually bilateral areas of ficult to determine because of limited transplant bonydestruction. 7, 11, 17, 18 Liu17reported that these le- experience with Hunter’s syndrome patients. We hope

PediatricDentistry - 17:2,1995 AmericanAcademy of PediatricDentistry 99 the future will provide more information and results in 4. Young1D, Harper PS: Long-termcomplications in Hunter’s this area. syndrome.Clin Genet 16:125-32, 1979. 5. YoungID, Harper PS, Archer IM, NewcombeRG: A clinical The most commonreasons for treatment failure are and genetic study of Hunter’s syndrome:I. Heterogeneity. infection, host rejection of the transplanted , and J MedGenet 19:401-7, 1982. graft-versus-host disease. Oral complications include 6. Hunter C: A rare disease in two brothers. Proc R Soc Med oral infection and mucositis. The most commoncause of 10:104-16,1917. morbidity and mortality during and after the transplan- 7. GardnerDG: The oral manifestations of Hurler’s syndrome. Oral Surg 32:46-57,1971. tation procedure is infection. It is therefore very impor- 8. YoungID, Harper PS: The natural history of the severe form tant to remove any possible source of oral infection prior of Hunter’s syndrome:a study based on 52 cases. Dev Med to transplantation and to maintain oral health. 19, 20 Child Neurol 25:481-89, 1983. Warkentin et al.20 have pointed out that post-BMT 9. YoungID, Harper PS: Mild form of Hunter’s syndrome: evaluations reveal notable but limited clinical improve- clinical delineation basedon 31 cases. ArchDis Child57:828- 36, 1982. ment. Longer followup is necessary in order to docu- 10. Stewart RE, Prescott GH:Oral facial manifestations of in- ment clinical improvement and sustain biochemical born errors of metabolism.Oral Facial Genetics. St Louis: correction. They point out that an extensive re-evalua- CVMosby Co, pp 392-96, 1976. tion is needed for one-year post-BMT. 11. LustmannJ, Bimstein E, Yatziv S: Dentigerous cysts and radiolucent lesions of the jaw associated with Hunter’s syn- drome. J Oral Surg 33:679-85, 1975. Conclusion 12. Clarke JT, Willard HF, Teshima I, ChangPL, Skomorowski Hunter’s syndrome is a very serious disease affect- MA:Hunter disease (mucopolysaccharidosis type II) in karyotypically normalgirl. Clin Genet37:355-62, 1990. ing children. Since few studies have been done on these 13. Neufeld EF, Liebaers J, Epstein CJ, Yatziv S, MilunskyA, children relating to bone marrow transplantation and Migeon BR: The Hunter syndromein females: is there an oral health, much more information is needed. For the autosomalrecessive formof iduronate sulfatase deficiency? children undergoing bone marrow transplantation, AmJ HumGenet 29:455-61, 1977. resto~g and maintaining health of the oral cavity is 14. Yatziv S, Erickson RP, Epstein CJ: Mild and severe (MPS II) within the same sibships. Clin Genet very important. Much more information is needed on 11:319-26,1977. the success-failure rate of bone marrow transplanta- 15. YoungID, Harper PS, NewcombeRG, Archer IM: A clinical tion in these children. and genetic study of Hunter’s syndrome. 2. Differences betweenthe mild and severe forms. J MedGenet 19:408-11, Dr. Downsis assistant professor in pediatric dentistry, University 1982. of Kentucky;Dr. Crisp is a pediatric dentist in Lexington; Dr. 16. Morehead JM, Parsons DS: Tracheobronchomalacia in Ferretti, is professor and director at KentuckyClinic Dentistry, Hunter’s syndrome. Intern J Pediatr Otorhino 26:255~1, University of Kentucky,Lexington. 1993. Wethank Mollie Young, Dr. Ted Raybould, and Dr. DougDamm. 17. Liu KL: The oral signs of Hurler-Hunter syndrome: report of four cases. ASDCJ Dent Child 47:122-27, 1980. 1. Dorfman A: Mucopolysaccharidoses. Nelson Textbook of 18. Reilly WA,Lindsay S: Gargoylism(lipochondrodystrophy) Pediatrics, llth ed. VaughanVC III, McKayRJ Jr, Behrman review of clinical observations in 18 cases. AmJ Dis Child RE, Eds. Philadelphia: WBSaunders Co, 1979, pp 1845-48. 75:595-607,1948. 19. 2. Gorlin RJ, CohenMM Jr, Levin LS: Mucopolysaccharidosis McDonaldRE, Avery DR: Bone marrowtransplantation. In: II. Syndromesof the Head and Neck, 3rd ed. NewYork: Dentistry for the Child and Adolescent,5th ed. St Louis: CV MosbyCo, pp 648-49, 1987. OxfordUniversity Press, 1990, pp 106-8. 3. LeRoyJG, Crocker AC:Clinical definition of the Hurler- 20. WarkentinPI, DixonMS Jr, Schafer I, Strandjord SE, Coccia PF: Bone marrowtransplantation in Hunter syndrome: a Hunter phenotypes -- a review of 50 patients. AmerJ Dis Child 112: 518-30, 1966. preliminary report. Birth Defects 22:31-39, 1986.

100 AmericanAcademy of Pediatric Dentistry PediatricDentistry - 17:2, 1995